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Objectives: Toothaches are often poorly localized. Although periodontal pain is better localized, it can spread to other areas. Ultimately, the cerebral cortex processes nociception, with somatotopic organization possibly playing a role in localizing the origin. However, the exact cortical area in the periodontal ligament (PDL) remains unclear., Methods: This study examined cortical responses to electrical stimulation of the molar PDL in anesthetized male mice using in vivo optical imaging with a voltage-sensitive dye, autofluorescent flavin fluorescence, and immunohistochemistry for c-Fos protein expression., Results: On optical imaging, cortical responses to the stimulation of the ipsilateral and contralateral PDL of the upper and lower teeth were observed in the primary somatosensory cortex (S1) and area from the insular cortex (IC) to the ventral edge of the secondary somatosensory cortex (S2), defined as the area caudal to the middle cerebral artery (C-area). Responses in S1 were faint and unstable, but were consistent in the C-area. The initial response locations were similar regardless of which PDL was stimulated, and the activated areas in the C-area almost overlapped. Three-dimensional construction of c-Fos-immunopositive cells responding to upper or lower PDL stimulation revealed bilateral distribution in the cingulate gyrus, secondary auditory cortex, temporal association cortex, ectorhinal cortex, and IC, but not in the S1 and S2., Conclusion: These results suggest that the somatotopic organization of the S1, S2, and IC cannot explain the localization of PDL nociception. The predominance of responses in the contralateral IC may provide clues for identifying the laterality., Competing Interests: Declaration of Competing Interest The authors declared no potential conflicts of interest with respect to the authorship and/or publication of this article., (Copyright © 2024. Published by Elsevier B.V.)

The physics of spin-orbit entangled magnetic moments of 4d and 5d transition metal ions on a honeycomb lattice has been much explored in the search for unconventional magnetic orders or quantum spin liquids expected for compass spin models, where different bonds in the lattice favour different orientations for the magnetic moments. Realising such physics with rare-earth ions is a promising route to achieve exotic ground states in the extreme spin-orbit limit; however, this regime has remained experimentally largely unexplored due to major challenges in materials synthesis. Here we report the successful synthesis of powders and single crystals of β-Na 2 PrO 3 , with 4f 1  Pr 4+  j eff  = 1/2 magnetic moments arranged on a hyperhoneycomb lattice with the same threefold coordination as the planar honeycomb. We find a strongly non-collinear magnetic order with highly dispersive gapped excitations that we argue arise from frustration between bond-dependent, anisotropic off-diagonal exchanges, a compass quantum spin model not explored experimentally so far. Our results show that rare-earth ions on threefold coordinated lattices offer a platform for the exploration of quantum compass spin models in the extreme spin-orbit regime, with qualitatively distinct physics from that of 4d and 5d Kitaev materials., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Prenylation of peptides is widely observed in the secondary metabolites of diverse organisms, granting peptides unique chemical properties distinct from proteinogenic amino acids. Discovery of prenylated peptide agents has largely relied on isolation or genome mining of naturally occurring molecules. To devise a platform technology for de novo discovery of artificial prenylated peptides targeting a protein of choice, here we have integrated the thioether-macrocyclic peptide (teMP) library construction/selection technology, so-called RaPID (Random nonstandard Peptides Integrated Discovery) system, with a Trp-C3-prenyltransferase KgpF involved in the biosynthesis of a prenylated natural product. This unique enzyme exhibited remarkably broad substrate tolerance, capable of modifying various Trp-containing teMPs to install a prenylated residue with tricyclic constrained structure. We constructed a vast library of prenylated teMPs and subjected it to in vitro selection against a phosphoglycerate mutase. This selection platform has led to the identification of a pseudo-natural prenylated teMP inhibiting the target enzyme with an IC 50 of 30 nM. Importantly, the prenylation was essential for the inhibitory activity, enhanced serum stability, and cellular uptake of the peptide, highlighting the benefits of peptide prenylation. This work showcases the de novo discovery platform for pseudo-natural prenylated peptides, which is readily applicable to other drug targets., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Rare-earth oxides have attracted interest as a platform for studying frustrated magnetism arising from bond-dependent anisotropic interactions. Ordered rock salt compounds Na 2 PrO 3 crystallize in two polymorphs (α and β) comprising honeycomb and hyperhoneycomb lattices of octahedrally coordinated Pr 4+ (4 f 1 ). Although possible realization of antiferromagnetic Kitaev interactions is anticipated for these phases on the basis of ab initio models, the air sensitivity of the two polymorphs has hampered reliable crystal growth and physical property measurements. Here, we have succeeded in preparing powder and single crystals of both α- and β-Na 2 PrO 3 using modified synthetic procedures. Revised crystal structures for both polymorphs are obtained from refinement of untwinned single-crystal X-ray diffraction data.

Background/aim: Nivolumab and ipilimumab combination therapy has been extensively explored for the treatment of advanced non-small-cell lung cancer (NSCLC) through the pivotal phase III trials CheckMate 227 and CheckMate 9LA. However, the relationship between immune-related adverse events (irAEs) and the effectiveness of nivolumab plus ipilimumab-based therapy in a real-world clinical setting remains uncertain., Patients and Methods: We performed a retrospective analysis of 28 patients with advanced or recurrent NSCLC who underwent treatment with nivolumab plus ipilimumab, with or without platinum-doublet chemotherapy, from February 2021 to January 2023. The primary objective was to elucidate the clinical association between irAEs and treatment efficacy associated with nivolumab plus ipilimumab-based therapy., Results: Among the 28 patients, 22 (78.6%) experienced irAEs. The median progression-free survival (PFS) was significantly longer for patients with irAEs than for those without (p=0.0158), as was overall survival (OS) (p=0.000394). The severity of irAEs had no significant influence on PFS or OS. The objective response rate tended to be higher in patients with irAEs than in those without (50.0% versus 0.0%, respectively; p=0.0549). Multivariate analysis indicated that irAE occurrence was an independent factor for improved PFS (hazard ratio=0.2084, p=0.01383) and OS (hazard ratio=0.0857, p=0.001588). Interstitial lung disease was inferior to other irAE profiles for both PFS and OS., Conclusion: Patients with advanced NSCLC experiencing irAEs demonstrated superior clinical outcomes when treated with nivolumab plus ipilimumab-based therapy compared with those without irAEs. However, immune-related interstitial lung disease may be less linked with PFS and OS than other irAE profiles., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim: In Japan, primary human papilloma virus (HPV) testing has not been introduced for cervical cancer screening due to concerns that HPV-negative lesions may be missed and a lack of Japanese data. The purpose of this study was to evaluate the validity of primary HPV testing in Japan by analyzing cervical intraepithelial neoplasia 2 (CIN2) or more/high-risk HPV- (CIN2+/hrHPV-) cases in cervical cancer screening., Methods: Data from 35 525 cervical cancer screenings with HPV testing and cervical cytology from 2011 to 2019 in Saga City, Japan, were reviewed. The cases with low-grade squamous intraepithelial lesion (LSIL+)/hrHPV- were analyzed in detail., Results: The results of the 35 525 examinees were as follows: 31 123 were negative for intraepithelial lesion or malignancy (NILM)/hrHPV-, 2612 were NILM/hrHPV+, 262 were atypical squamous cells of undetermined significance (ASC-US)/hrHPV-, 213 were ASC-US/hrHPV+, 291 were LSIL+/hrHPV-, and 1024 were LSIL+/hrHPV+. Of the 256 LSIL+/hrHPV- examinees for whom histology was available, CIN2+ were CIN2 9.4% (24/256), CIN3 3.9% (10/256), cervical adenocarcinoma 0.4% (1/256), uterine corpus cancer 1.2% (3/256), and uterine sarcoma 0.4% (1/256). Overall, the rate of LSIL+/hrHPV- was 0.82% (291/35.525), 0.1% (36/35525) of which were cervical lesions with CIN2+. Only one cervical adenocarcinoma was detected, but gastric-type adenocarcinoma was not included., Conclusion: HPV-negative CIN2+ or cervical adenocarcinoma is not a concern for the introduction of primary HPV screening in Japan. Primary HPV testing in cervical cancer screening is considered a feasible method that can be used in Japan, although an algorithm suitable for Japan and a national-level management system need to be established., (© 2023 Japan Society of Obstetrics and Gynecology.)

The Seirei dysphagia screening questionnaire (namely, Seirei dsq) has been used to screen for oropharyngeal dysphagia (OD). Some of the questions in the questionnaire are difficult for people with cognitive decline to answer. We selected 10 items from the Seirei dsq that could be assessed by others, such as care workers (named Swallow-10). This study aims to verify the validity of the scoring method used in Swallow-10. The dataset used in this study was the one used in the development of Seirei dsq : 50 patients with cerebrovascular disease who were diagnosed with OD, 145 patients with cerebrovascular disease who did not have OD, and 170 healthy subjects. Among the answer choices, "A" for severe symptom, "B" for mild symptom and "C" for no symptom were scored with 4, 1 and 0 points respectively. Factor analysis extracted two factors : one related to pharyngeal function and another related to oral function. In addition, the Cronbach's alpha coefficient was 0.84. ROC analysis indicated that optimal cutoff value was 5 points, with a sensitivity of 90.0% and a specificity of 88.5%. These results suggest that Swallow-10 may be useful as an OD screening tool for subjects with cognitive decline J. Med. Invest. 70 : 231-235, February, 2023.

Aim: This study aimed to clarify (1) the effectiveness of human papillomavirus (HPV) vaccine against precancerous lesions of uterine cervical cancer and (2) the difference in these effectiveness based on smoking status., Methods: This retrospective cross-sectional study considered women aged 20-24 who underwent cervical cancer screening in Saga City from April 2014 to March 2020. Cervical cytology and histological diagnosis were compared with or without HPV vaccination and smoking., Results: The study included 7253 women (2467 vaccinated and 4786 unvaccinated). Among the vaccinated women, 462 were smokers, 2003 were nonsmokers: among the nonvaccinated women, the numbers were 1217 and 3554, respectively. 0.28% (7/2467) of participants with vaccination had HSIL+ compared to 0.77% (37/4786) without vaccination (odds ratio [OR] 0.36, 95% confidence interval [CI], 0.16-0.81). About 0.32% (8/2467) with vaccination had cervical intraepithelial neoplasia (CIN) 2+ compared to 0.69% (33/4786) without vaccination (OR 0.46, 95% CI, 0.21-1.00). Four women without vaccination had CIN3+. In nonsmokers, HPV vaccination significantly suppressed the incidence of HSIL+ from 0.42% (15/3554) to 0.1% (2/2003) (OR 0.21, 95% CI, 0.05-0.95), but the suppressive effect was not significant in smokers (OR 0.59, 95% CI, 0.22-1.56). In vaccinated women, the incidence of CIN2+ was 0.20% (4/2003) in nonsmokers and 0.87% (4/462) in smokers (OR 0.22, 95% CI, 0.05-0.89, p = 0.02)., Conclusions: HPV bivalent/quadrivalent vaccination is effective in protecting against CIN but insufficient in smokers. The nine-valent vaccine should be introduced into routine vaccination as soon as possible to prevent high-risk HPV infection other than 6/11/16/18., (© 2022 Japan Society of Obstetrics and Gynecology.)

Dimensionality is a critical factor in determining the properties of solids and is an apparent built-in character of the crystal structure. However, it can be an emergent and tunable property in geometrically frustrated spin systems. Here, we study the spin dynamics of the tetrahedral cluster antiferromagnet, pharmacosiderite, via muon spin resonance and neutron scattering. We find that the spin correlation exhibits a two-dimensional characteristic despite the isotropic connectivity of tetrahedral clusters made of spin 5/2 Fe 3+ ions in the three-dimensional cubic crystal, which we ascribe to two-dimensionalisation by geometrical frustration based on spin wave calculations. Moreover, we suggest that even one-dimensionalisation occurs in the decoupled layers, generating low-energy and one-dimensional excitation modes, causing large spin fluctuation in the classical spin system. Pharmacosiderite facilitates studying the emergence of low-dimensionality and manipulating anisotropic responses arising from the dimensionality using an external magnetic field., (© 2021. The Author(s).)

Background: Seromucinous borderline tumor (SMBT) is a rare neoplasm which was newly defined in the 2014 WHO classification. Although the clinical and histopathological characteristics of SMBT have been well described, its cytological characteristics have not. We recently experienced 2 cases of SMBT which were defined by cytological findings of ascites., Case Presentation: Case 1 was a 65-year-old Japanese woman. Preoperative imaging studies revealed abundant ascites and a cystic tumor, with a solid component measuring 13 cm on the left ovary. Radical surgery was performed during the intraoperative diagnosis of ovarian borderline tumor, made by histological examinations of frozen tumor sections. The cytological smears of preoperatively and intraoperatively collected ascites showed many atypical cells resembling reactive mesothelial cells. Alcian-blue staining of cell block sections revealed intracytoplasmic mucin, and the results of immunohistochemistry were consistent with SMBT. The final pathological diagnosis of tumor was SMBT. Case 2 was a 28-year-old Japanese woman. Preoperative imaging studies revealed a small amount of ascites and cystic tumors with solid components in the bilateral ovaries. She initially underwent fertility preservation surgery. SMBT was suspected by cytological examination of smears of intraoperatively collected ascites and the findings of cell block. She underwent additional radical surgery based on a final pathological diagnosis of SMBT., Conclusion: In our experience, the tumor cells of SMBT in ascites mimicked reactive mesothelial cells. The nuclear atypia of SMBTs was intermediate between that of reactive mesothelial cells and serous carcinoma. The immunohistochemistry and mucin staining using cell block were very helpful for facilitating the cytodiagnosis of SMBT., (© 2021 S. Karger AG, Basel.)

Here we report the construction of an mRNA-encoded library of thioether-closed macrocyclic peptides by using an N-chloroacetyl-cyclopropane-containing exotic initiator whose structure is more constrained than the ordinary N-chloroacetyl-α-amino acid initiators. The use of such an initiator has led to a macrocycle library with significantly suppressed population of lariat-shaped species compared with the conventional libraries. We previously used a conventional library and identified a small lariat thioether-macrocycle with a tail peptide with a C-terminal free Cys whose sidechain plays an essential role in potent inhibitory activity against a parasitic model enzyme, phosphoglycerate mutase. On the other hand, the cyclopropane-containing macrocycle library has yielded a larger thioether-macrocycle lacking a free Cys residue, which exhibits potent inhibitory activity to the same enzyme with a different mode of action. This result indicates that such a cyclopropane-containing macrocycle library would allow us to access mechanistically distinct macrocycles., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A bibliographic search was conducted of cases of Candida endophthalmitis reported in Japan and overseas between 2000 and 2011, in the Japana Centra Revuo Medicina Website of Japan Medical Abstracts Society (domestic reports) and MEDLINE (overseas reports). The investigation yielded 42 reports in domestic journals (49 cases ; hereinafter referred to as domestic cases) and 39 reports in journals published overseas (46 cases ; hereinafter referred to as overseas cases). The isolation rate of Candida albicans in the domestic cases was 65.3%, and that in the overseas cases was 71.7%. The initial treatment for the Candida endophthalmitis was fluconazole (FLCZ) therapy in 51.0% of the domestic cases and 38.1% of the overseas cases. Domestic reports suggested the effectiveness of FLCZ therapy for stage II cases, and of vitrectomy for stage III and IV cases. Reports from overseas, on the other hand, suggested the effectiveness of amphotericin B (AMPH-B) or voriconazole (VRCZ) therapy for stage II cases, and of vitrectomy for stage III and IV cases.

Design: Randomized controlled study., Setting: Laboratory., Participants: 26 healthy swimmers randomly assigned to an exercise (n = 13; Ex) or control group (n = 13; Cont)., Intervention: The Ex group performed respiratory-muscle exercises for 10 min thrice a week for 4 wk., Context: Respiratory-muscle exercises are used not only in the rehabilitation of patients with respiratory disease but also in endurance training for athletes. Respiration involves the back and abdominal muscles. These muscles are 1 of the elements responsible for posture control, which is integral to injury prevention and physical performance. However, the effects of respiratory-muscle exercise on posture remain unclear., Objective: To examine the potential of respiratory-muscle exercise for improving posture., Main Outcome Measures: Spinal curvature, pulmonary function, and trunk-muscle strength were measured for both the groups at baseline and after 4 wk. The data were compared between the Ex and Cont groups with Mann-Whitney U test and preintervention and postintervention within groups with a Wilcoxon signed rank-sum test., Results and Conclusion: The spinal curvature was significantly different in the Ex group, indicating a decrease in the thoracic (-13.1%, P < .01) and lumbar (-17.7%, P < .05) angles. The Ex group presented with lower thoracic (-8.6%) and lumbar (-20.9%) angles at postexercise than the Cont group (P < .05). With respect to trunk-muscle strength, only trunk-flexion strength significantly increased from pretest to posttest in the Ex group (P < .05). For pulmonary function, forced vital capacity and forced expiratory volume in 1.0 s were significantly increased after 4 wk in the Ex group (P < .05). The results suggest that respiratory-muscle exercise straightened the spine, leading to good posture control, possibly because of contraction of abdominal muscles.

Objective: The contents of bererine, palmatine and glycyrrhizin acid in Banxiaxiexintang decoction of different combinations were determined by PR-HPLC., Method: A Shim-pack CLC-ODS column was used with a mobile phase of CH3CN-H2O (31:69; 0.005 moL.L-1 -pentanesulfonic acid sodium salt, H3PO4: pH 3.0) for bererine andpalmatine, which were detected at the wavelength of 275 nm. A YWG-C18 column was used with a mobile phase of CH3OH-H2O-HAc(62:37:1) for glycyrrhizin acid which was detected at the wavelength of 260 nm., Result: Each herbs' combination influences the contents of the 3 components., Conclusion: The experiment is an attempt to study the comical foundation of traditional Chinese prescription.

A case of a 44 year old female with inferior vena cava thrombosis associated with cholelithiasis was reported. The patient had chest and back pain due to pulmonary embolism. Ultrasonic examination showed stone echoes in the gallbladder and thrombus echoes in the inferior vena cava (IVC) at the height from renal veins to bifurcation of iliac veins, but iliofemoral thrombosis was not found by RI angiography and venography. Anticoagulant and urokinase were administered, then pulmonary embolus disappeared and IVC thrombus reduced. IVC thrombus was removed by incision of IVC. Thrombus was white thrombus. Etiology of thrombus was not clear. IVC ligation or plication for prevention of pulmonary emboli was not carried out. Etiology, diagnosis and treatment of IVC thrombosis were also discussed.

Xanthogranulomatous cholecystitis is rare, and information on its radiologic diagnosis is limited. Radiologic findings of seven patients with histologically proven xanthogranulomatous cholecystitis were reviewed retrospectively. Sonography showed a calculus or calculi of the gallbladder with moderate thickening of the wall in all. IV cholangiography was performed in six cases. Findings were nonspecific. Four had nonopacified gallbladder, and one had stenosis of the proximal part of the common bile duct. Marked thickening of the gallbladder wall was seen in six of seven cases on CT. In one case the thickened wall was lobulated and irregular. The border between the gallbladder and the adjacent liver was unclear in two and relatively clear in five. Four patients underwent angiography to evaluate the possibility of tumor. Two of them had irregularity and stenosis of the cystic artery highly suggestive of carcinoma. The other two showed only dilatation of the cystic artery. On the basis of all radiologic studies, carcinoma was diagnosed preoperatively in two of the seven cases. Radiologically, xanthogranulomatous cholecystitis may best be regarded as a tumor-like condition and should be included in the differential diagnosis of gallbladder cancer.